Positive allosteric modulation of α5-GABA A Receptor in the 5XFAD mouse model has cognitive and neurotrophic benefits

Abstract

INTRODUCTIONReduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimers disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through 5-GABA-A receptors (5-GABAA-R). 5-GABAAR positive allosteric modulation (5-PAM) has procognitive and neurotrophic effects in stress and aging models. METHODSWe tested whether 5-PAM (GL-II-73) could reverse cognitive deficits and neuronal spine loss in early and late stages of {beta}-amyloid deposition in the 5xFAD model (N=48/study; 50% female). RESULTSAcute or chronic administration of GL-II-73 reversed spatial working memory in 5xFAD mice at 2 and 5 months of age. Chronic GL-II-73 treatment reversed 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite {beta}-amyloid accumulation. DISCUSSIONThese results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related {beta}-amyloid deposition. This suggests 5-PAM as a novel {beta}-amyloid-independent symptomatic therapeutic approach.